The present invention relates to new non-estrogenic derivative compounds of estradiol with antioxidative activity.
It is known from the patent literature, namely from DE 43 38 314 C1, that estradiol and its known derivatives with phenolic A-rings and 17-hydroxy groups have fundamental antioxidative activity. These substances have a more or less strong binding affinity to estrogen receptor sites according to their structure. The high affinity of natural 17xcex2-estradiols (100%) is usually considerably decreased by structural changes, such as isomerization or derivativization. However it still amounts to 23% for 17xcex1-estradiol and it is still 8.6% for the enantiomer of the natural estradiol, 8xcex1, 9xcex2, 14xcex2-estra-1,3,5(10)-trien-3,17xcex1-diol (ent-estradiol). These values are not always tolerable depending on the dosage and application duration during administration of the substances with the aim to increase the body""s antioxidative capacity.
When a large substituent is introduced at the 17-carbon atom according to German Patent Document DE 43 38 316 A1, for example in 17xcex1-4xe2x80x2-dimethylamino-phenylmethyl-estra-1,3,5(10),9(11)-tetraen-3,17-diol, the binding affinity can be reduced up to less than 1% while increasing the antioxidative activity. However in vivo a high estrogen activity was found for the corresponding 3-methyl ether, 3-methoxy-17xcex1-4xe2x80x2-dimethylamino-phenylmethyl-estra-1,3,5(10)-trien-17-ol.
It is an object of the present invention to provide new estradiol derivative compounds with antioxidative activity having no estrogenic activity.
According to the invention, the non-estrogenic estradiol derivative compounds with antioxidative activity include the compounds of the following formula (I): 
wherein R1 is H or OH,
R2 and R3 are the same or different and are each, independently of each other, H or CH3,
R4 and R5 are the same or different and are each, independently of each other, xe2x80x94OH, xe2x80x94O(CO)R6, xe2x80x94OR6 or xe2x80x94OSO2NR7R8, wherein R6 represents an aryl group or an alkyl group having 1 to 4 carbon atoms, and the R7 and R8 groups are each, independently of each other, H or an alkyl group having one to four carbon atoms, or R7 and R8 together with the N atom represent a polymethylenimino group with 4 to 6 carbon atoms or a morpholino group,
each of the dashed lines represents either an additional bond or not in the ring positions indicated by the respective dashed lines so that either a double bond or a single bond is present at the respective ring positions;
but with the proviso that the compounds of formula I do not include 4-methyl-estra-1,3,5(10)-trien-1,17xcex2-diol;
and the non-estrogenic estradiol derivative compounds with antioxidative activity also include the compounds of the following formula (II): 
xe2x80x83wherein R1 is H or OH,
R2 and R3 are the same or different and are each, independently of each other, H or CH3,
Z is an unsubstituted group represented by (CH2)nAPh, wherein Ph represents a phenyl group and A represents a bond for n=0 or a bond, O, S or Se for n=1, or Z is a 17xcex1-substituent group containing a phenyl group, Ph, having from 1 to 2 hydroxy group substituents and 0 to 2 methyl group substituents or a dimethylaminophenyl group and 0 to 2 methyl group substituents;
R4 and R5 are the same or different and are each, independently of each other, xe2x80x94OH, xe2x80x94O(CO)R6, xe2x80x94OR6 or xe2x80x94OSO2NR7R8, wherein R6 represents aryl group or an alkyl group having 1 to 4 carbon atoms, and the R7 and R8 groups are each, independently of each other, H or an alkyl group having one to four carbon atoms, or R7 and R8 together with the N atom represent a polymethylenimino group with 4 to 6 carbon atoms or a morpholino group, and
each of the dashed lines represents either an additional bond or not in the ring positions indicated by the respective dashed lines so that either a double bond or a single bond is present at the respective ring positions.
The preferred compounds of the invention are:
4-methyl-estra-1,3,5(10)-trien-1,17xcex1-diol,
4-methyl-estra-1,3,5(10),6-tetraen-1,17xcex1-diol,
4-methyl-estra-1,3,5(10),6-tetraen-1,17xcex2-diol,
4-methyl-estra-1,3,5(10),6,8-pentaen-1,17xcex2-diol,
4-methyl-estra-1,3,5(10),6,8-pentaen-1,17xcex1-diol,
17xcex1-4xe2x80x2-hydroxyphenylmethyl-4-methyl-estra-1,3,5(10)-trien-1,17xcex2-diol,
17xcex1-4xe2x80x2-hydroxy-phenoxymethyl-4-methyl-estra-1,3,5(10)-trien-1,17xcex2-diol,
17xcex1-4xe2x80x2-hydroxy-thiophenoxymethyl-4-methyl-estra-1,3,5(10)-trien-1,17xcex2-diol,
17xcex1-4xe2x80x2-dimethylamino-phenylmethyl-4-methyl-estra-1,3,5(10)-trien-1,17xcex2-diol,
17xcex1-3xe2x80x2,5xe2x80x2-dimethyl-4xe2x80x2-hydroxy-phenylmethyl-4-methyl-estra-1,3,5(10)-trien-1,17xcex2-diol.
17xcex1-3xe2x80x2,5xe2x80x2-dimethyl-4xe2x80x2-hydroxy-phenylmethyl-4-methyl-estra-1,3,5(10),6-tetraen-1,17xcex2-diol and
17xcex1-4xe2x80x2-hydroxy-phenoxymethyl-4-methyl-estra-1,3,5(10),6-tetraen-1,17xcex2-diol.
It was surprisingly found that these compounds, regioisomers of estradiol and their derivatives, which have a phenolic hydroxy group on carbon atom 1 and a hydroxy group on carbon atom 17, are neither estrogens in vitro nor in vivo, as shown in Tables 1 and 2. At the same time these compounds have an antioxidative activity that is clearly increased in comparison to estradiolxe2x80x94as demonstrated in Tables 3 and 4.
Since the substances have an intact steroid framework and a polarizability comparable to the natural estrogens, it is expected that the ability to penetrate the blood-brain barrier and for membrane-receptor exchange remain the same as in the natural estrogens.
The estradiol derivative compounds according to the invention, in which the estrogeneity is practically completely eliminated while improving the antioxidative activity, are potentially suitable for use as non-estrogenic antioxidants, especially for administration to post-menopausal women and in men. The absence of estrogen action is also advantageous when the inhibition of enzymes generating estrogens is the aim of a therapeutic strategy, especially the inhibition of aromatase and sulfatase. The enzymes, aromatase and sulfatase, release estrone from estrone sulfate. A strong inhibition of sulfatase by sulfamates of the currently known phenolic steroids according to M. J. Reed, et al, xe2x80x9cSteroid Sulphatase Inhibitor: A new endrocrine therapyxe2x80x9d, Drugs Future 19 (1994), p. 673, and W. Elger, et al, xe2x80x9cSulfamates of various estrogens are prodrugs with increased systemic and reduced hepatic estrogenicity at oral applicationxe2x80x9d, J. Steroid Biochem. Biol., 55, (1995), p. 395 to 403. This leads to inhibition of release of estrone from estrone sulfate in vitro and in vivo. The compounds according to the invention are thus also potential inhibitors of aromatase and sulfatase.